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Cancer in Pregnancy: Management of complications associated with cancer or antineoplastic treatment during pregnancy

Professional Summary
The treatment of choice for a large spectrum of hypercoagulable states during pregnancy is heparin. As an alternative, and probably a therapy that will become the future's 1st line choice are the low molecular weight heparins.

Coumarin is not an option during pregnancy for the majority of the cases.

Erythropoietin does not cross the placenta and is associated with minimal side effects to the mother that are generally well tolerated. No fetal complications were reported.

The data regarding the safety of bisphosphonates and hematopoietic growth factors during pregnancy is scarce, and no firm recommendation can be made at this time.

Most antibiotics are not contraindicated during pregnancy, with the exception of the use of tetracycline during the 2nd and 3rd trimester.

Most of the analgesics are quite safe during pregnancy, as no malformations were noticed with first trimester use of most of them. Their main effect of narcotics analgesics is on fetal respiratory system, and these newborns should be watched carefully during delivery for signs of withdrawal or respiratory depression.

Introduction
Cancer is the second leading cause of death in women during the reproductive years. Its incidence is between 0.07% to 0.1% of pregnancies. The diagnosis of cancer during pregnancy imposes major therapeutic decisions -- optimal maternal treatment must be balanced against the risks to the fetus. The malignant disease and its treatment have specific complications that may have special importance during pregnancy. These include, among others, bone marrow depression with neutropenia and infections, anemia and thrombocytopenic bleeding. Both pregnancy and cancer are associated with hypercoagulability and thromboembolism. Also, skeletal manifestations of cancer like osteoporosis, bone pain, pathological fractures and hypercalcemia may require specific treatment during pregnancy. Thus, these complications of cancer or its treatment may expose the pregnant woman to additional medications including anticoagulants, antibiotics, analgesics and new treatment modalities such as hematopoietic growth factors and bisphosphonates. This is a general overview of the use of these therapeutic measures during pregnancy.

Anticoagulants Heparin

Heparin is a natural, water soluble, mucopolysaccharide which is being used for almost 80 years. Heparin exerts most of its anticoagulant activity by binding to antithrombin III, a naturally occurring anticoagulant. This complex inhibits a number of coagulation factors, mainly IIa and Xa. Other coagulation factors - IX, XI, XII are also inhibited. Heparin does not cross the placenta in appreciable amounts. No reports linking the use of heparin during gestation with congenital defects have been located.

In a review of the literature of fetal outcome following anticoagulant therapy during pregnancy, 86 publications reporting fetal outcome in 1325 pregnancies were collected. A series of analysis was performed across three groups: anticoagulation with heparin alone, oral anticoagulation with coumadin, and the use of both heparin and coumadin. The data were analyzed in four ways in order to identify clinically important fetal/infant outcomes caused by anticoagulation. The first analysis summarized all reported adverse fetal/infant outcome events. The second sub-group analysis was performed with the aim to exclude adverse fetal/infant outcomes which could have been caused by maternal comorbid conditions. A third sub-group analysis aimed at excluding from the second group premature births in which the infants did not suffer from permanent disabilities.

A fourth sub-group analysis analyzed only deaths (abortions, stillbirths and neonatal deaths after excluding maternal comorbid conditions. Adverse fetal/infant outcomes were 21.7%, 10.4%, 3.6%, and 2.5%, respectively, a much lower percent compared to the coumarin group (27.9%, 26.5%, 26.1%, 16.8%, respectively). In a separate analysis of patients with venous thromboembolism but using the same four sub-groups, adverse fetal/infant outcomes were 13.3%, 9%, 3%, and 2.6% for the heparin group, respectively, and 18.7%, 16.9%, 16.9%, and 8.5%, respectively, for the coumadin group. Thus, the previously reported high frequency of adverse effects of heparin is explained by maternal comorbid conditions (pre-eclampsia, glomerulonephritis, placental insufficiency) that independently are associated with adverse effects. Heparin is considered to be safe during pregnancy for either the prevention or treatment of thromboembolic disease.

Low molecular weight heparins
Low molecular weight heparins (LMWH) are formed by enzymatic depolymerization of heparin. Their molecular weight is between 4000-6000 Dalton. These LMWH or fractionated heparins have emerged during recent years as an effective antithrombotic treatment-either as prophylaxis or as therapy for a variety of thromboembolic conditions. Due to their different structure, the major difference between LMWH and unfractionated heparin lies in their relative inhibitory activity against factor Xa and thrombin.

The main advantages of LMWH over unfractionated heparin are their predictable anticoagulant activity. Thus, no laboratory monitoring is necessary. The incidence of bleeding is less with LMWH than with unfrationated heparins, as well as their tendency to induce thrombocytopenia associated with paradoxical thrombosis. The efficacy and paucity of complications make LMWH a promising anticoagulant.

In a number of both animal and human studies, no transfer of LMWH through the placenta was demonstrated by comparing anti-Xa and anti-IIa activities in the mothers and their fetuses. Clinical experience with LMWH as prophylaxis for thromboembolic phenomena in pregnancy was addressed in a number of studies. No thromboembolic complications occurred, no side effects were observed and all the babies were born healthy. Two recent publications on the safety of LMWH during pregnancy in thrombosis-prone women are reassuring.

In summary, the administration of LMWH during pregnancy is safe for both the mother and the fetus. The absence of teratogenic effects, a predictable anticoagulation, easy administration and lack of need for laboratory monitoring make them preferable for thromboembolism during pregnancy. They can be administered to pregnant women with cancer for both prevention and treatment.

Oral anticoagulants -- Coumarin
Oral anticoagulants cross the placenta and can enter the fetal circulation. Since 1966 when the first case of "coumarin embryopathy" was described, the literature regarding the adverse outcome of the fetus following maternal exposure to coumarin has expanded. Most of the reports addressed the following problems associated with the use of coumarin during pregnancy: embryopathy, central nervous system defects, stillbirth, spontaneous abortions, prematurity and hemorrhage. The characteristics of fetal warfarin syndrome associated with first trimester exposure to coumarin are nasal hypoplasia due to maldevelopment of the nasal septum and stippled epiphyses, depression of the nasal bridge with a flattened upturned appearance. Eye defects, seizures, deafness, congenital heart disease, and hypoplasia of the extremities have all been reported.

Exposure to warfarin during any trimester resulted in central nervous system abnormalities.

Two main patterns were reported: 1. Dorsal midline dysplasia with agenesis of the corpus callosum, Dandy-Walker malformations and midline cerebellar atrophy. 2. Ventral midline dysplasia characterized by optic atrophy.

In summary, the use of oral anticoagulants during first trimester is associated with an increased rate of fetal wastage and congenital malformations. The use of warfarin in any trimester carries an increased risk of central nervous system defects. In our view, coumadin should not be used during pregnancy unless heparin or LMWH are strongly contraindicated due to a serious adverse effect in the mother (severe thrombocytopenia, paradoxical thrombosis).

G-CSF and GM-CSF
The clinical use of these growth factors include a variety of situations in which rapid neutrophil recovery is needed. As they have been shown to decrease the periods of hospitalization, duration of infection or antibiotic administration and the period of neutropenia, their use has been approved by the FDA for the treatment of patients with prespecified indications after chemotherapy for non-myeloid malignancies. They are also employed today for other conditions like bone marrow transplantation or various causes of bone marrow depression.

Clinical experience with GM-CSF and G-CSF during pregnancy is very limited. The teratogenicity was studied in rats at dose levels of 250, 500 and 1000 mcg/kg/day, from day 7 to day 17 and from day 17 to day 21 post delivery. As compared to controls the incidence of anomalies was not significantly increased in the fetuses. No effect was found on parturition, lactation, post- natal growth and reproductive ability.

Maternally administered rhG-CSF has been shown to cross the placenta during 3rd trimester and induce granulopoiesis in neonatal rats.

In a pilot study, a single dose of 25mcg/kg of rhG-CSF was given to women with imminent delivery and their controls. Transplacental passage of G-CSF was most noticeable in those women who received G-CSF at least 30 hours before delivery.

In summary, it can be concluded that transplacental transfer of G-CSF and GM-CSF is observed in different stages of pregnancy. No teratogenicity was observed in animal model. The information in humans is very limited; so far, no teratogenic effects were reported.

Erythropoietin
Erythropoietin is a glycoprotein with a molecular weight of 30400 Dalton produced primarily by the kidneys. Hypoxia increases the production of the hormone, which enhances red blood cell proliferation. Erythropoietin is remarkably specific for the erythroid progenitor cells with little effect on other cells. Therapy with recombinant human erythropoietin was first shown to correct the anemia caused by end-stage renal failure in dialysis patients. Obviously, cancer during pregnancy by itself or due to different treatment modalities can result in reduced hemoglobin levels.

Physiologic erythropoietin levels increase gradually and peak during third trimester. With a molecular weight of 30400 erythropoietin is not expected to cross the placenta. This is supported by the lack of association between fetal and maternal erythropoietin levels during pregnancy and at birth, but conflicting results do exist with regard to the possibility of placental transfer. In animal studies, no teratogenic effects were noticed at doses used in humans, although the administration of high doses (500 U/kg) was shown to cause birth defects.

Blood transfusions carry both immediate and long term complications and hazards.

In contrast, the complications of erythropoietin are mild and include flu like syndrome which is usually self-limited, conjunctival inflammation and, in small percentage, seizures. Developing or worsening hypertension which was reported during erythropoietin treatment in patients with renal failure, was not reported in pregnant women. Treatment of pregnant women with erythropoietin may obviate theneed for multiple blood transfusions.

There is little information in the literature on the use of erythropoietin during pregnancy. No large controlled studies exist, and most of the information is reported as case reports or case series.

In summary, erythropoietin administration during pregnancy is considered to be safe. It does not seem to cross the placenta and no teratogenic effects were found among the small number of women treated during organogenesis. No worsening or new onset hypertension were observed.

Thus erythropoietin can probably be safely used in the treatment of anemia related tomalignancy during pregnancy.

Bisphosphonates
Pregnant women with cancer may have hypercalcemia. Hematological malignancies (multiple myeloma, lymphoma) as well as solid tumors (breast, kidney, lung) can be associated with hypercalcemia which is a medical emergency. Also, painful bone metastasis or severe osteoporosis may occur during the course of neoplastic disease.

Bisphosphonates are a group of compounds with high affinity for bone and are concentrated in areas of high bone turnover. Their mechanism of action is thought to be inhibition of osteoclast activity. The experience with bisphosphonates during pregnancy is very limited. There are no controlled studies in pregnant women, and most of the information comes from animal studies.

These studies have shown that most of bisphosphonates cross the placenta when dams were given high dose of the drug (10-35 times the human dose), as evident by their ability to bind to fetal bone and cause skeletal abnormalities. The main adverse effect found in animal reports was their ability to decrease maternal calcium, which caused protracted parturition due to uterine contraction, a calcium-dependent process. This effect on parturition in the dams was associated with neonatal deaths. Intravenous calcium supplementation prevented the above-described adverse effects. Thus, in animals, the bisphosphonates- induced hypocalcemia is the main cause of maternal toxicity, rather than a direct effect on the pups.

In summary, the information regarding the safety of bisphosphonates use during pregnancy is scarce and is mainly derived from animal studies and a handful human reports. The side effects reported in animals are of concern. The data in humans are scarce and prevents any firm recommendation. If the drug is used, careful monitoring of calcium level in the mother and the fetus are advised.

Antibiotics
As the pregnant woman with malignancy might be treated with a single or combination of antibiotics, their effects on either the mother or the child should be known. Penicillins, cephalosporins and erythromycin are considered the antibiotics of choice during pregnancy, with wide safe margin. Aminoglycosides, sulfonamides, and metronidazole are not contraindicated during pregnancy and can be used when indicated. Quinolones were blamed for causing arthropathy in children but are not teratogenic-they should be probably avoided during pregnancy, and future studies will shed light on their effect on cartilage formation. Perhaps the only antibiotics that should be avoided during second and third trimester are tetracyclines due to their effects on teeth and bone, although no teratogenicity was shown to occur with these drugs.

Analgesics
Acetaminophen is widely used during pregnancy for pain relief and as antipyretic due to its efficacy and minimal side effects. It crosses the placenta and believed to be non-teratogenic in therapeutic doses. By monitoring 50,282 mother-child pairs, 226 of which had 1st trimester exposure to acetaminophen, no evidence was found for increased risk of birth defects due to acetaminophen. It is important to remember that as acetaminophen crosses the placenta, the fetus is theoretically at risk from maternal overdose. The antidote, N-acetylcystein was demonstrated to cross the placenta.

Aspirin has been shown by many studies to be the drug most frequently used during pregnancy. Consumption of aspirin during pregnancy may produce adverse effects in the mother, such as anemia, hemorrhage and prolonged gestation and labor. A number of retrospective controlled and surveillance studies which included a large number of patients did not find any association between aspirin use during 1st trimester and teratogenic effects.

Low dose aspirin is used to treat a variety of conditions such as systemic lupus erythematosus with lupus anticoagulant/anti phospholipid antibody syndrome to reduce the incidence of pregnancy loss, pregnancy-induced hypertension, preeclampsia/eclampsia and others. No fetal or neonatal toxicity was observed after chronic use of low dose aspirin. The use of high dose aspirin in the second half of pregnancy is more controversial. The main concerns being: 1) its anti-prostaglandin effects associated with increased bleeding during delivery and bleeding complications in the fetus; 2) premature closure of the ductus arteriosus; 3) oligohydroamnion. In summary, it may be desirable to discontinue aspirin one to two weeks prior to term to avoid aspirin-induced bleeding problems. If high dose aspirin is used during the second half of pregnancy, amniotic fluid volume and patency of fetal ductus arteriosus should be monitered by fetal cardiac ultrasound.

Indomethacin, Ibuprofen, Naproxen, Ketorolac and other NSAIDS are not considered teratogenic in animals or humans. Due to their effects on prostaglandins, they may cause premature closure of the ductus arteriosus, oligohydroamnion and bleeding complications. They are effective as tocolytic agents and have been used for the treatment of premature labor. They should be used with caution near term and careful follow-up for amniotic fluid volume and the patency of the ductus are mandatory.

Codeine is a widely used narcotic analgesic and antitussive. Many cold preparations and over-the counter medications contain codeine. It is not associated with a higher risk of congenital malformations in animals. In higher dose (100 mg/kg/day), fetal resorption, decreased fetal body weight and maternal toxicity were observed. Use of codeine near term may cause a narcotic withdrawal syndrome in the newborn, manifested as tremor, jitteriness, diarrhea and poor feeding. During labor, neonatal respiratory depression can occur to the same magnitude as other narcotics.

Meperidine is not associated with increased incidence of birth defects. However, in light of its effect on fetal respiratory system, heart rate, and oxygen consumption, caution should be used when administered during labor. Also, withdrawal symptoms and neonatal addiction are possible when used inappropriately during pregnancy.

Morphine, an opioid analgesic, is not considered to be teratogenic in humans. Placental transfer of morphine is very rapid. As with other narcotics maternal addiction with subsequent signs of neonatal withdrawal are expected in chronic users. Respiratory depression, decreased oxygen consumption in the newborn were all observed in children born to mothers who received morphine during labor or used the drug chronically. Persistent behavioral abnormalities attributed to morphine alone have not been proven in humans.

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